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Originally published In Press as doi:10.1074/jbc.M200826200 on July 22, 2002

J. Biol. Chem., Vol. 277, Issue 41, 38133-38140, October 11, 2002
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Adhesion-related Kinase Repression of Gonadotropin-releasing Hormone Gene Expression Requires Rac Activation of the Extracellular Signal-regulated Kinase Pathway*

Melissa P. AllenDagger §, Mei XuDagger §, Daniel A. Linseman§, John E. PawlowskiDagger §, Gary M. Bokoch||, Kim A. Heidenreich§, and Margaret E. WiermanDagger §**Dagger Dagger

From the Departments of Dagger  Medicine,  Pharmacology, and ** Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado 80262, the § Research Service, Veterans Affairs Medical Center, Denver, Colorado 80220, and the || Departments of Immunology and Cell Biology, Scripps Research Institute, La Jolla, California 92037

Recent studies suggest that adhesion-related kinase (Ark) plays a role in gonadotropin-releasing hormone (GnRH) neuronal physiology. Ark promotes migration of GnRH neurons via Rac GTPase and concomitantly suppresses GnRH gene expression via homeodomain and myocyte enhancer factor-2 (MEF2) transcription factors. Here, we investigated the signaling cascade required for Ark inhibition of the GnRH promoter in GT1-7 GnRH neuronal cells. Ark repression was blocked by the MEK/ERK pathway inhibitor, PD98059, and dominant negative MEK1 but was unaffected by dominant negative Ras. Inhibitors of the Rho family GTPases, Clostridium difficile toxin B (Rho/Rac/Cdc42 inhibitor) and Clostridium sordellii lethal toxin (Rac/Cdc42 inhibitor), blocked Ark inhibition of GnRH transcription. Moreover, dominant negative Rac blunted both Ark activation of ERK and repression of the GnRH promoter, demonstrating an essential role for Rac in coupling Ark to ERK activation. Like Ark, a constitutively active mutant of Rac suppressed GnRH transcription in an ERK-dependent manner. Finally, Ark-mediated repression was significantly attenuated by a dominant negative MEF2C, whereas repression induced by constitutively active Rac was unaffected, indicating that MEF2 proteins are not targets of the Ark right-arrow Rac right-arrow MEK right-arrow ERK cascade. The data suggest that Ark suppresses GnRH gene expression via the coordinated activation of a Rac right-arrow ERK signaling pathway and a distinct MEF2- dependent mechanism.

* This work was supported by National Institutes of Health Grants HD31191-04 (to M. E. W.), HD08667-02 (to M. P. A.), GM44428 (to G. M. B.), by the Veterans Affairs Research Enhancement Award program (to K. A. H. and D. A. L.), and by the Veterans Affairs Merit Review (to M. E. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Dagger To whom correspondence should be addressed: Veterans Affairs Medical Center, 1055 Clermont St., Box 111H, Denver, CO 80220. Tel.: 303-399-8020 (ext. 3150); Fax: 303-393-5271; E-mail: margaret.wierman@uchsc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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